AChE inhibitors and substrates (Part II)

Treatment of Alzheimer's disease
Alzheimer's disease (AD) is a disorder that attacks the central nervous system through progressive degeneration of its neurons. Patients with this disease develop dementia which becomes more severe as the disease progresses. It was suggested that symptoms of AD are caused by decrease of activity of cholinergic neocortical and hippocampal neurons. Treatment of AD by ACh precursors and cholinergic agonists was ineffective or caused severe side effects. ACh hydrolysis by AChE causes termination of cholinergic neurotransmission. Therefore, compounds which inhibit AChE might significantly increase the levels of ACh depleted in AD. Indeed, it was shown that AChE inhibitors improve the cognitive abilities of AD patients at early stages of the disease development. The first generation of AD drugs were AChE inhibitors: alcaloids like (-)-Huperzine A (HupA) and (-)-galanthamine (GAL, Reminyl); synthetic compounds tacrine (Cognex) and rivastigmine (Exelon).



(-)-Huperzine A
(-)-Huperzine A, discovered by Chinese scientists from 1980s, has been proved to be a powerful, highly specific, and reversible inhibitor of AChE. It is a novel alkaloid originally isolated from the Traditional Chinese medicine Qian Ceng Ta which is produced from the whole plant of the firmossHuperzia serrata. Qian Ceng Ta has been used for over 1000 years in China for treatment of contusions, strains, swellings, schizophrenia and myasthenia gravis. Shuangyiping, a tablet form of HupA produced from the extracts of Huperzia serrata, was developed in 1996 as a new drug for symptomatic treatment of Alzheimer’s disease in China. Compared with the other three FDA-approved drugs for the treatment of Alzheimer’s disease, Donepezil (Aricept), Rivastigmine (Exelon), Galanthamine (Reminyl), HupA has better penetration through the blood-brain barrier, higher oral bioavailability, and longer duration of AChE inhibitory action. The structure of HupA shows some similarity to other known AChE inhibitors. The molecule is fairly rigid and contains an aromatic system as well as a primary amino group that is probably protonated at physiological pH. Various suggestions have been made with respect to its orientation within the active site of AChE, and with respect to the amino acid residue with which its putative pharmacophoric groups might interact. Solution of the 3D structure of a complex of HupA with AChE would permit unequivocal resolution of this issue and it would also provide a rational basis for structure-related drug design aimed at developing synthetic analogues of HupA with improved therapeutic properties.

The crystal structure of the complex of TcAChE with HupA at 2.5 Å resolution (1vot) was determined in 1997 and it shows an unexpected orientation for the inhibitor with surprisingly few strong direct interactions with protein residues to explain its high affinity. HupA binds to TcAChE at the active site, and its observed orientation is almost orthogonal in comparison to ACh. The principal interactions of HupA with TcAChE are including: a direct hydrogen bond with Tyr130 and HBs with Glu199 and Gly117 (colored orange) through a water molecule as a linker at the bottom of the gorge; cation-π interactions between the amino group of HupA and Trp84 and Phe330 (colored lime) with the distance between the nitrogen and the centroid of the aromatic rings of 4.8 and 4.7 Å, respectively; at the top of the gorge, hydrogen bonds through two water molecules as linkers formed between the amino group of HupA and Tyr70, Asp72, Ser81, Asn85 and Tyr121 (colored magenta). An unusually short (~3.0 Å) C-H→O HB has been seen between the ethylidene methyl group of HupA and the main chain oxygen of His440 (colored crimson).

Tacrine
Tacrine. In the X-ray crystal structure of TcAChE/tacrine complex which was determined at 2.8 Å resolution, the tacrine is seen (magenta) bound in the active site of TcAChE (1acj). <font color='gray'>ACh (gray) is shown for comparison.

Huprine X
<scene name='1e66/Active_site/1'>Huprine X (HUPerzine A + tacRINE) is one of the most potent reversible AChE inhibitors. This <scene name='1e66/Active_site/2'>synthetic hybrid consists of a carbobicyclic moiety resembling that of (−)-<scene name='1e66/Active_site/12'>huperzine A <font color='blueviolet'>(colored blueviolet) and the 4-aminoquinoline substructure of <scene name='1e66/Active_site/7'>tacrine <font color='magenta'>(colored magenta). Both these compounds are known AChE inhibitors. <font color='blueviolet'>(−)-Huperzine A and <font color='magenta'>tacrine positions partially overlap each other at the TcAChE <scene name='1e66/Active_site/13'>active site. TcAChE residues interacting with (−)-huperzine A (1vot) <font color='orange'>are colored orange and with tacrine (1acj) <font color='cyan'>are colored cyan. The <scene name='1e66/Active_site/10'>conformation of the 4-aminoquinoline substructure of the huprine X in its complex with TcAChE (1e66, TcAChE interacting residues are in <font color='lime'>lime ) is very similar to that of tacrine. The ring system of (−)-huperzine A is <scene name='1e66/Active_site/14'>rotated almost 180° relative to that of huprine X.

Galanthamine
<scene name='AChE_inhibitors_and_substrates/Com_view_gal/1'>Galanthamine (GAL). <scene name='AChE_inhibitors_and_substrates/Com_view_gal/2'>GAL <font color='red'>(red) is an alkaloid from the flower snowdrop (Galanthus nivalis). The X-ray crystal structure of the TcAChE/GAL complex (1dx6) was determined at 2.3 Å resolution. The inhibitor binds at the base of the active site gorge of TcAChE, interacting with both the choline-binding site (Trp84) and the acyl-binding pocket (Phe288, Phe290). The tertiary amine appears to make a non-conventional hydrogen bond, via its N-methyl group, to Asp72. The hydroxyl group of the inhibitor makes a strong hydrogen bond (2.7 Å) with Glu199. <font color='gray'>ACh (gray) is shown for comparison.

Edrophonium
<scene name='2ack/Com_view/1'>Edrophonium (EDR) is stacked between the aromatic rings of <scene name='2ack/Com_view/2'>W84 and F330, near the TcAChE <scene name='2ack/Com_view/3'>catalytic triad which consists of <font color='magenta'>'S200' , <font color='magenta'>'E327' , and <font color='magenta'>'H440' (2ack).

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Additional Resources
For additional information, see: Alzheimer's Disease

For information about additional AChE monovalent inhibitors please see AChE inhibitors and substrates (Part III).